Pembrolizumab (PD-1) + Definitive RT Improves 2-Year PFS vs Cisplatin CRT in Unfavorable-Risk p16+ HNSCC (KEYCHAIN)

KEYCHAIN was an open-label, randomized Phase II trial across 6 US academic centers testing definitive RT (70 Gy/35 fx) plus concurrent/adjuvant pembrolizumab (anti–PD-1; 200 mg starting 2 weeks pre-RT, then q3w up to 20 cycles) vs standard concurrent cisplatin-RT (100 mg/m² q3w) in newly diagnosed unresected “unfavorable-risk” p16+ HNSCC (mostly oropharynx; modified ITT n=102: pembro n=50, cis n=52; median follow-up 26.5 months). Two-year PFS was 84% vs 70% (HR 0.57; 95% CI 0.25–1.31; 1-sided p=0.09, meeting the protocol’s 1-sided α=0.15), and 2-year OS was 98% vs 85% (HR 0.33; 95% CI 0.09–1.28; 1-sided p=0.048); grade ≥3 treatment-related AEs were 36% vs 46%—not a dramatic de-tox signal, but directionally favorable. Versus definitive cisplatin-RT benchmarks in HPV+/p16+ OPC (commonly ~97% 2-year OS in low-risk populations), KEYCHAIN’s cisplatin arm looks meaningfully worse—consistent with the “unfavorable-risk” enrichment—making the absolute PFS/OS deltas for pembro-RT clinically interesting if they hold up.